Currently, polyethylene glycol derivatives are widely used to be combined with proteins, polypeptides, and other therapeutic drugs to prolong the physiological half life of the drugs and reduce immunogenicity and toxicity thereof. In clinical application, PEG and derivatives thereof have been widely used in many drugs as carriers for the production of pharmaceutical preparations, while the study of bonding of PEG with drug molecules has also been developed rapidly in the last decade, polyethylene glycol has a quite clear metabolic processes in the human body, and is a safe synthetic polymer material with no side effects.
As a safe synthetic polymer material with no side effects, polyethylene glycol has been widely used in production of new medical devices. Such as CoSeal from Baxter, SprayGel and DuraSeal from Covidien, are all new medical devices appear on the United States or European market in recent years, using a multi-arm polyethylene glycol.
In the modification of drugs, compared with straight-chain polyethylene glycol, multi-arm polyethylene glycol has a plurality of terminal groups, thus has an advantage of having a plurality of drug connecting points and loading a plurality of drug molecules. At present, multi-arm polyethylene glycol has been widely used in PEGylation modification of polypeptides and small molecule drugs. In the medical device applications, multi-arm polyethylene glycol can be used as a crosslinking agent, applied in production of a gel. These gels can be used as a binder, anti-leakage agent, anti-blocking agent and hemostatic material in medical devices.
Patent WO2011075953A1 discloses a new multi-arm polyethylene glycol having different types of reactive groups, formed by polymerizing ethylene oxide with oligo-pentaerythritol as an initiator, the reactive terminal group thereof is selected from: hydroxyl, amino, sulfydryl, carboxyl, ester group, aldehyde group, acrylic group and maleimide group, which are all short-chain substituents.
CN101747192B discloses a method for synthesizing a polyethylene glycol oleate, obtained by esterification reaction of polyethylene glycol (PEG) with oleic acid used as raw materials under the action of an organic acid catalyst, however, polyethylene glycol polymers prepared by this method have a low polymerization degree and a molecular weight of 400-1,000, and only monooleate or dioleate can be obtained by this method.
CN103145968A discloses a folate-conjugated polyethylene glycol monostearate and preparation method and application thereof, it can be seen from its molecular structure that the product obtained is only a monostearate, and due to the limitation of the linking group, this patent only discloses that polyethylene glycol monostearate can be conjugated with the drug folic acid.
To overcome the deficiencies in the prior art, the present application provides a stearic acid derivative and oleic acid derivative of multi-arm polyethylene glycol and preparation method thereof.